Objective: To examine the causal association and potential mechanisms between bone mineral density in different age groups and primary malignant bone tumor based on two sample Mendelian randomization (MR), so as to provide a reference for the prevention and treatment of primary malignant bone tumor. Methods: The genome-wide association study (GWAS) of bone mineral density was obtained from the GEFOS database,which included 66 628 subjects divided into five age groups (0-15, 15-30, 30-45, 45-60, and >60 years) based on the phases of human bone development. The GWAS of primary malignant bone tumor was sourced from the FinnGen database, including 648 cases and 378 749 controls. Using bone mineral density of five age groups as the exposure and primary malignant bone tumor as the outcome, an MR analysis was performed with the inverse-variance weighted (IVW) method. Sensitivity analysis were conducted using Cochran's Q test, MR-Egger regression, MR-PRESSO test and MR Steiger test. The potential mechanisms underlying the causal association between bone density and primary malignant bone tumors were explored using Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Results: The MR analysis results showed that there was a negative causal association between bone density and primary malignant bone tumors in the 30-45 age group (OR=0.301, 95%CI: 0.126-0.721). No statistically significant associations between bone density and primary malignant bone tumors were found in the 0-15, 15-30, 45-60, and >60 age groups (all P>0.05). Sensitivity analysis did not detect heterogeneity, pleiotropy (all P>0.05) and reverse causality. KEGG enrichment analysis revealed that genes highly associated with bone density and primary malignant bone tumors were enriched in the mTOR signaling pathway and the Wnt signaling pathway, among which Low Density lipoprotein Receptor Related protein 5 and Wnt Family Member 16 are key regulatory genes. Conclusion The decrease in bone mineral density among individuals aged 30-45 may increase the risk of primary malignant bone tumors through the mTOR signaling pathway and the Wnt signaling pathway.

Lipotoxicity is a pivotal factor that initiates and exacerbates liver injury and is involved in the development of metabolic-associated fatty liver disease (MAFLD). However, there are few reported lipotoxicity inhibitors. Here, we identified a natural anti-lipotoxicity candidate, HN-001, from the marine fungus Aspergillus sp. C1. HN-001 dose- and time- dependently reversed palmitic acid (PA)-induced hepatocyte death. This protection was associated with IRE-1α-mediated XBP-1 splicing inhibition, which resulted in suppression of XBP-1s nuclear translocation and transcriptional regulation. Knockdown of XBP-1s attenuated lipotoxicity, but no additional ameliorative effect of HN-001 on lipotoxicity was observed in XBP-1s knockdown hepatocytes. Notably, the ER stress and lipotoxicity amelioration was associated with PLA2. Both HN-001 and the PLA2 inhibitor MAFP inhibited PLA2 activity, reduced lysophosphatidylcholine (LPC) level, subsequently ameliorated lipotoxicity. In contrast, overexpression of PLA2 caused exacerbation of lipotoxicity and weakened the anti-lipotoxic effects of HN-001. Additionally, HN-001 treatment suppressed the downstream pro-apoptotic JNK pathway. In vivo, chronic administration of HN-001 (i.p.) in mice alleviated all manifestations of MAFLD, including hepatic steatosis, liver injury, inflammation, and fibrogenesis. These effects were correlated with PLA2/IRE-1α/XBP-1s axis and JNK signaling suppression. These data indicate that HN-001 has therapeutic potential for MAFLD because it suppresses lipotoxicity, and provide a natural structural basis for developing anti-MAFLD candidates.

Humans ; Dyslipidemias ; HIV Infections/drug therapy* ; Risk Factors

Humans ; Immune Checkpoint Inhibitors/therapeutic use* ; Prospective Studies ; HIV Infections/drug therapy* ; Anti-HIV Agents/therapeutic use* ; Comorbidity

Objective : To explore the method of using high-fat diet combined with angiotensin-Ⅱ ( Ang-Ⅱ) and β-aminopropionitrile (BAPN) to establish the model of aortic dissection in mice． Methods : 24 C57BL /6J mice (4 weeks old，male) were randomly divided into control group［intraperitoneal injection of 0．9% sodium chloride solu- tion 10 ml / (kg · d) ］and experimental groups［Ang-Ⅱ 4 mg / ( kg · d) group，Ang-Ⅱ 4 mg / ( kg · d) + BAPN 0. 33 g / (kg · d) group］，each group with 8 mice ; all mice were given a high-fat diet and the mice weights were measured at the same time point and administered according to the weight standard．The dead mice were dissected immediately and the aorta was taken out for pathological section，then observed under the microscope．The morphology of aorta was detected by small animal ultrasound and the mice with obvious dissection were killed and dissected directly. Results : After administration，the activity and appetite of mice in the high-fat diet combined with Ang-Ⅱ + BAPN group decreased most significantly，and the mortality rate of aortic dissection rupture and the success rate of modeling in this group were higher than those in the high-fat diet combined with Ang-Ⅱ group，while there was no significant change in the control group．Under the ultrasound of small animals，compared with the other two groups，the mice in the high-fat diet combined with Ang-Ⅱ + BAPN group showed the formation of abdominal aortic vascular false lumen and vascular enlargement．The mice that died during the administration were dissected immediately，and a large number of blood clots in the abdominal cavity and around the blood vessels could be seen．The mice with aortic dissection or aortic aneurysm could be seen under ultrasound in small animals，and severe adhesion between the vascular wall and the surrounding tissues could be found when dissected，while no obvious abnormalities were found in the blood vessels of the control group．The results of the staining showed that the false lumen of blood vessel wall was formed and the arrangement of elastin and collagen was disordered in the mice of high fat diet com- bined with Ang-Ⅱ + BAPN group．The thickness of blood vessel wall in each group was statistically analyzed，and it was found that the blood vessels in the two experimental groups were thicker than those in the control group，which was statistically significant (P＜0. 001) ．The vascular wall of Ang-Ⅱ + BAPN + high-fat diet group showed severe elastin degradation． Conclusion High-fat diet combined with Ang-Ⅱ 4 mg / (kg · d) and BAPN 0. 33 g / (kg · d) can establish an efficient model of aortic dissection in mice.

OBJECTIVE To validate the anticancer effect of Angong Niuhuang pill (AGNH) and pinpoint associated molecular mechanisms using human cancer cells.METHODS Human MGC-803 gastric carcinoma and human BEL-7402 hepatocarcinoma cells were incubated with AGNH 9,30,90,300 and 900 mg·L-1 for 24,48and 72 h,respectively.Cell viability was detected with 3-(4,5-dimethylthiazol-2-yl) -5-( 3-carboxymethoxyphe-nyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and colony formation assay.Apoptosis was measured with flow cytometry and Hoechst 33258/PI staining.Change in mitochondrial membrane potential (△qψ) was detected by spectrofluorophotometer.RESULTS AGNH inhibited MGC-803 cell proliferation ( for 48 h,r =0.996,P =0.002; for72 h,r=0.756,P=0.024 ) and BEL-7402 cells (for 48 h,r =0.732,P=0.030; for72 h,r=0.702,P =0.037) in a concentration-dependent manner,as showed by MTS assay.AGNH inhibited colony formation on MGC-803 cells (r =0.914,P =0.011 ) and BEL-7402 cells (r =0.871,P =0.024) in a concentration-dependent manner for 24 h.Hoechst 33258/PI staining and flow cytometry assay showed that AGNH 900 mg·L-1 for 24 h induced apoptosis of MGC-803 and BEL-7402 cells,and the apoptosis rate was 27.2％ and 19.7％,respectively.Compared with normal control group,AGNH 900 mg·L-1 for 3 min decreased the mitochondrial membrane potential of MGC-803 and BEL-7402 cells to 15.9％ and 15.0％ of control group.CONCLUSION AGNH inhibits proliferation of human cancer cells.Apoptosis and depolarization of mitochondrial transmembrane potential are probablly its mechanism.

OBJECTIVETo investigate anticancer effect and potential mechanism of tanshinone II(A) (Tan II(A)) on human nasopharyngeal carcinoma cell line CNE cells.

METHODAntiproliferative effect of Tan II(A) on CNE cells was evaluated by morphological examination, cell growth curves, colonial assay and MTT assay. Apoptosis detection was carried out using Hoechest 33258 and PI double-dyeing method. Intracellular Ca2+ concentration and mitochondria membrane potential were detected by fluorospectrophotometer. Bad and MT-1A transcript analysis in CNE cells was analyzed by real-time reverse transcriptase-polymerase chain reaction (RT-PCR).

RESULTTan II(A) could inhibit CNE cells proliferation in dose- and time-dependent manner. 50% inhibiting concentration of Tan II(A) on CNE cells in 24, 48, 72 h was 45.7, 24.8, 3.3 mg x L(-2), respectively. Typical apoptotic morphology such as chromatin aggregation was observed in CNE cells with Tan II(A) treated for 24 h, and the apoptotic inducing effect was in a dose-dependent manner. After treated with Tan II(A), intracellular Ca2+ concentration of CNE cells was increased, mitochondria membrane potential of the cells was decreased, relative mRNA level of Bad and MT-1A was up-regulated.

CONCLUSIONTan II(A) had anticancer effect on CNE cells through apoptosis via calcineurin-dependent pathway and MT-1A downregulation.

Antineoplastic Agents, Phytogenic ; pharmacology ; Apoptosis ; drug effects ; Calcium ; metabolism ; Carcinoma ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Diterpenes, Abietane ; pharmacology ; Drugs, Chinese Herbal ; pharmacology ; Gene Expression Regulation, Neoplastic ; drug effects ; Humans ; Membrane Potential, Mitochondrial ; drug effects ; Metallothionein ; genetics ; Nasopharyngeal Neoplasms ; genetics ; metabolism ; pathology ; Signal Transduction ; drug effects ; bcl-Associated Death Protein ; genetics

AIM:To study the role of prostaglandin F2?(PGF2?) in cardiac hypertrophy and its relation with calcineurin(CaN) signal transduction pathway in vitro.METHODS:The cultured neonatal rat cardiomyocyte was used to observe the hypertrophic effect of PGF2?,and the hypertrophic response was assayed by measuring the cell diameter,protein content and atrial natriuretic factor(ANF) mRNA expression.For mechanism studies,the intracellular free calcium concentration([Ca2+]i) in cultured cardiomyocytes was measured by using Fura-2/AM as a fluorescent indicator.ANF and CaN mRNA expressions,and the expressions of CaN and its downstream effectors,NFAT3 and GATA4 proteins were assayed by RT-PCR and Western blotting,respectively.RESULTS:In cultured cardiomyocytes,PGF2? induced profound hypertrophic morphology change and the significant increase in cell diameter,and protein content in a concentration-dependent manner compared with those in vehicle control(P